The preparation of 1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[ b,d]pyran-9-ones was first reported by Fahrenholtz, Lurie and Kierstead, J. Am. Chem. Soc., 88, 2079(1966); 89,5934(1967). The reported synthesis provided predominantly the dl-6a,10a-trans compound, with minor quantities of the corresponding dl-6a,10a-cis isomer being isolated. The compounds were used by Fahrenholtz et al. only as intermediates, and no pharmacological activity was attributed to them. It recently has been discovered that such hexahydrodibenzopyranones have a variety of useful biological properties, and accordingly are valuable in the treatment of various mammalian disorders. U.S. Pat. Nos. 3,953,603, 3,944,673, and 3,928,598, describe the use of hexahydrodibenzopyranones in the treatment of anxiety, depression, and for imparting analgesia. Particular attention is drawn to dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-9H-dib enzo[b,d]pyran-9-one, an especially potent drug generically referred to as Nabilone.
It now has been learned that certain dl-trans-hexahydrodibenzopyranones are more active pharmacologically than the corresponding dl-cis-isomers. Further resolution of such dl-trans racemates has led to the discovery that essentially all of the biological activity displayed by a dl-trans-hexahydrodibenzopyranone is possessed by the optically active isomers wherein the 6a and 10a hydrogen atoms both have the R absolute configuration. The optically active trans isomers wherein the 6a and 10a hydrogen atoms both have the S absolute configuration are particularly useful as intermediates in the synthesis of compounds having valuable central nervous system activity. It therefore becomes desirable to have a stereoselective synthesis of such optically active trans-hexahydrodibenzopyranones.
A stereospecific synthesis leading to (-)-.DELTA..sup.1 -THC has been reported by Mechoulam, Braun and Gaoni, J. Am. Chem Soc., 89, 4552 (1967). Such synthetic path started with optically active (-)-verbenol, which was condensed with a 5-substituted resorcinol. Such method is not applicable to the synthesis of hexahydrodibenzopyranone derivatives since the latter compounds have a 9-keto group rather than a methyl substituent as in the Mechoulam et al. process.